Abstract：
Metastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti-resistance agents to current treatment protocols can potentially improve clinical responses. Myocardin-related transcription factor (MRTF) is a transcriptional coactivator whose activity is indirectly regulated by actin and the Rho family of GTPases. We previously demonstrated that development of BRAF inhibitor (BRAFi) resistance frequently activates the Rho/MRTF pathway in human and mouse BRAFV600E melanomas. In clinical trials, pretreatment with BRAFi reduces the benefit of immune therapies. We aimed to test the efficacy of concurrent treatment with our MRTF pathway inhibitor CCG-257081 and anti-PD1 in vivo and to examine its effects on the melanoma immune microenvironment. Because MRTF pathway activation upregulates the expression of immune checkpoint inhibitor genes/proteins, we asked whether CCG-257081 can improve the response to immune checkpoint blockade. CCG-257081 reduced the expression of PDL1 in BRAFi-resistant melanoma cells and decreased surface PDL1 levels on both BRAFi-sensitive and -resistant melanoma cells. Using our recently described murine vemurafenib-resistant melanoma model, we found that CCG-257081, in combination with anti-PD1 immune therapy, reduced tumor growth and increased survival. Moreover, anti-PD1/CCG-257081 co-treatment increased infiltration of CD8+ T cells and B cells into the tumor microenvironment and reduced tumor-associated macrophages. Here, we propose CCG-257081 as an anti-resistance and immune therapy-enhancing anti-melanoma agent.
摘要：
转移性皮肤黑色素瘤是一种致命的皮肤癌。对靶向和免疫疗法的抗性限制了当前治疗的益处。在当前的治疗方案中识别和添加抗耐药剂可以潜在地改善临床反应。Myocardin相关转录因子（MRTF）是一种转录共激活因子，其活性受肌动蛋白和GTP酶的Rho家族间接调节。我们先前证明了BRAF抑制剂（BRAFi）抗性的发展经常激活人和小鼠BRAFV600E黑色素瘤中的Rho/MRTF途径。在临床试验中,用BRAFi预处理降低了免疫疗法的益处。我们旨在测试我们的MRTF途径抑制剂CCG-257081和抗PD1在体内同时治疗的功效，并检查其对黑色素瘤免疫微环境的影响。因为MRTF通路激活上调免疫检查点抑制剂基因/蛋白的表达,我们询问CCG-257081是否可以改善对免疫检查点阻断的应答.CCG-257081降低了PDL1在BRAFi抗性黑素瘤细胞中的表达,并降低了BRAFi敏感性和抗性黑素瘤细胞中的表面PDL1水平。使用我们最近描述的鼠维罗非尼耐药黑色素瘤模型，我们发现CCG-257081联合抗PD1免疫治疗，减少肿瘤生长和增加生存率。此外，抗PD1/CCG-257081共同治疗增加了CD8+T细胞和B细胞向肿瘤微环境的浸润,并减少了肿瘤相关巨噬细胞。这里,我们建议CCG-257081作为抗耐药和增强免疫治疗的抗黑色素瘤药物.
